Process for preparing 1-(tetraacyl-d-ribitylamino)-4, 5-dimethylbenzene



Patented Feb. 22, 1944 UNITED STATES PATENT OFFICE PROCESS FOR PREPARING l-(TETRAACYL- d RIBITYLAMINO) ZENE - 4,5 DIMETHYLBEN- Max- Tishler, Rahway, N. .L, and John W. Wellman, Cleveland Heights, Ohio, asslgnors to Merck & Co., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Appllcation June 18,1941, Serial No. 398,584. In Canada January 13, 1941 8 Claims. (Cl. 260- 211) as represented by Formula I, derivatives of 1,2-

diamino-4,5-dimethylb'enzene having an acylated pentose radical substituted in one of the amino groups as represented by Formula II, and derivatives of 1-amlno-2-arylazo-4,5-dimethyl benzene having an acylated pentose radical substituted on the amino group as represented by Formula III, are valuable intermediates for preparing tetraacyl riboflavin, or riboflavin.

wherein R is an acyl radical, and R1 is an aryl radical.

We have also discovered .that tetraacyl-dribonic acid nitrile reacts readily with l-amino- 4,5-dimethylbenzene in the presence of hydrogen and a hydrogenation catalyst such as Pd,

Pt, and Ni to give Compound I. This substance may be coupled with diazotized paranitro aniline, diazotized benzidine, or other diazotized aryl amines to produce compounds represented by Formula III. Compounds of this class can be condensed with barbiturlc acid to form fiavins.

Another method of preparing fiavins from compounds represented by Formula II: is to reduce the azo compounds, for example, by catalytic hydrogenation, to compounds represented by Formula II. The latter compounds react readily with halo barbituric acids to give the corresponding fiavins. In addition, such compounds readily react with alloxan to give flavins.

The following example illustrates methods of carrying out our present invention, but it is to be understood that this example is given by way of illustration and not of limitation.

Example A hydrogenating bottle is charged with 8 gins. of '4,5-dimethylaniline, 0.5 gm. of hydroquinone, 0.5 gm. of anhydrous sodium acetate and 1 gm. of palladium oxide. The bottle is then placed in a hydrogenation Eapparatus and fitted with a separatory tunnel, which is kept at about 50" u.

A warm solution of 10.5 gms. of tetraacetylribononitrile in 30 cc. of methyl alcohol is then allowed to drop in slowly while hydrogenation is occurring. The addition of the nitrile solution requires about six hours. After all of the nitrile is added, the mixture is shaken with hydrogen for about one hour longer and then filtered. The filtrate is seeded and kept at -50 C. The 1.-N- (tetraacetyl-d-ribitylamino) 4, 5 dimethylbenzene separates as fine needles, M. P. 97-98 C. Additional quantities oi the product may be obtained from the mother liquor by diluting with water, extracting with ether and diluting with petroleum ethen. Yield 5.5 'gms. The unreacted dimethylaniline may be recovered by concentrating the ether-petroleum ether solution and distilling the residue in vacuum.

3.34 ms. of p-nitroaniline hydrochloride is dissolved by warming in a solution of 3 cc. of concentrated hydrochloric acid in 3 cc. of water. The hot solution is added to cc. of water with stirring and the mixture cooled to 10 C. At this temperature, with stirring, 1.65 gms. of sodium nitrite in 20 cc. of water are added rather rapidly and the mixture allowed to stand for 1 /2 hours. During this time, nearly all of the nitroaniline hydrochloride goes into solution. The

excess of nitrous acid is then destroyed by adding urea, the mixture is filtered from small amounts of insoluble material, and the filtrate is then added rapidly to a stirred solution of 5 guns. oi 1-tetraacetyl-d-ribityl-amino-4,5 d-imethylbenzene in cc. of acetic acid. After the addition,

' which the azo compound" goes into solution and a colorless solution is obtained. The mixture is filtered and concentrated to dryness, and i- (tetraacctyl-d-ribitylamino) 2 amino 4,5-dimethylbenzene' is recovered.

Other acyl derivatives may be obtained by employing diilerent acyi compounds as starting materials.

Modifications may be made in carrying out the present invention. without departing from the spirit and scope thereof, and we are .to limited only by the appended claims.

We claim:

1 The process comprising reacting tetraacyld-ribonic acid nitrile. and l-amino-4,5-dimethylbenzene in the presence of hydrogen and a hydrogenation catalyst to produce l- (tetraacyld-ribitylamino) 4,5-dimethylbenzene.

2. The process comprising reacting tetraacetyld-ribonic acid nitrile, and l-amino-4,5-dimethylbenzene in the presence of hydrogen and a hydrogenation catalyst to produce l-(tetraactyld-ribitylamino) -4,5-dimethylbenzene.

3. The process comprising'reacting tetraacyb d-ribonic acidnitrile, and l-amino-4,5-dimethylbenzene in the presence of hydrogen and a hydrogenation catalyst comprising palladium to produce l-(tetraacyl-d-ribitylamino) 4,5-dimethylbennene.

4. The process comprising reacting tetraacyld-ribonic acid nitrile. and l-amino-4,5-dimeth-' ylhenzene in the presence of hydrogen and a hydrogenation catalyst comprising platinum to produce 1 (tetraacyl-d-ribitylamino) 4,5-diylbenzene in the presence of hydrogen and a hydrogen catalyst comprising palladium to pro- I duce. l- (tet raacetyl-d-ribitylamino) -4,5-dimethylbenzene.

"L The process comprising reacting tetraacetyldribonic acid nitrile, and l-amino-4,5-dimethylbenzene in the presence of hydrogen and a hydrogenation catalyst comprising platinum to produce I-(tetraacetyl-d-ribitylamino)-4,5-dimethylbenzene.

8. The process comprising reacting tetraacetyl-d-ribonic acid nitrile, and 1-amino-4,5-dimethylbenzene in the presence of hydrogen and a hydrogenation catalyst comprising nickel to produce l-(tetraacetyl-d-ribitylamino)-4,5-dimethylbenzene.

MAX TISHLER.

JOHN W. WELL-MAN.

CERTIFICATE or connzcnon. Patent No. 2,5u2,l+58. February 22, 191m.

m nsnmn, ET AL.

It is hereby certified that error appears in the printed epeeificutipn of the above numbered pa tenfi requiring correction as follows:' Page 1, second. 001mm, line a0, for "-5o a." read -5 c. page 2, first c61- umn, line 27, claim 2, for 'tetraacty1- read tetraacetyk line 35, claim 3, for "1-(tetraacylfil-ribitylamino) 1;,5-d1-f' read 1-(Fetraacyld-ribitylnmino) -u,5-a1- and second column, 1111016, claim .6, for""hydrogen reald "hydrogenation"; line :19-20, claim 7,' .ior "liBtIQlCQtYlrflIibonic" rend --tetraacety 1 -d-r1 bonicand that the aeid Lettei'e Pltent ahould be read with this cer'rection thez ein th t the e. may canton; to the recorpl of the case in the Patent office.

Signed and sealed th1e9th day or my, A, D. 191m.

Leslie Frazer (sen) Acting Commissioner of Patents. 

